CN115770225B - Cardiglutamic acid freeze-dried solid preparation and preparation method thereof - Google Patents
Cardiglutamic acid freeze-dried solid preparation and preparation method thereof Download PDFInfo
- Publication number
- CN115770225B CN115770225B CN202211496715.1A CN202211496715A CN115770225B CN 115770225 B CN115770225 B CN 115770225B CN 202211496715 A CN202211496715 A CN 202211496715A CN 115770225 B CN115770225 B CN 115770225B
- Authority
- CN
- China
- Prior art keywords
- acid
- freeze
- kaglutamic
- aqueous solution
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002253 acid Substances 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- 239000007787 solid Substances 0.000 title claims abstract description 43
- 239000007864 aqueous solution Substances 0.000 claims abstract description 39
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims description 54
- 238000001816 cooling Methods 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 36
- 238000010438 heat treatment Methods 0.000 claims description 35
- 238000000859 sublimation Methods 0.000 claims description 29
- 230000008022 sublimation Effects 0.000 claims description 29
- 238000004108 freeze drying Methods 0.000 claims description 27
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 24
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 24
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 22
- 238000007710 freezing Methods 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- 238000002347 injection Methods 0.000 claims description 19
- 239000007924 injection Substances 0.000 claims description 19
- 239000000337 buffer salt Substances 0.000 claims description 18
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 11
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 11
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 11
- 239000005492 Carfentrazone-ethyl Substances 0.000 claims description 10
- MLKCGVHIFJBRCD-UHFFFAOYSA-N ethyl 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propanoate Chemical group C1=C(Cl)C(CC(Cl)C(=O)OCC)=CC(N2C(N(C(F)F)C(C)=N2)=O)=C1F MLKCGVHIFJBRCD-UHFFFAOYSA-N 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 5
- 235000013922 glutamic acid Nutrition 0.000 claims description 5
- 239000004220 glutamic acid Substances 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- 150000003013 phosphoric acid derivatives Chemical group 0.000 claims description 3
- 235000019846 buffering salt Nutrition 0.000 claims description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940111685 dibasic potassium phosphate Drugs 0.000 claims 1
- 239000012931 lyophilized formulation Substances 0.000 claims 1
- 229940111688 monobasic potassium phosphate Drugs 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 20
- 238000000137 annealing Methods 0.000 description 11
- LCQLHJZYVOQKHU-VKHMYHEASA-N carglumic acid Chemical compound NC(=O)N[C@H](C(O)=O)CCC(O)=O LCQLHJZYVOQKHU-VKHMYHEASA-N 0.000 description 11
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 10
- 235000019797 dipotassium phosphate Nutrition 0.000 description 10
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 239000012528 membrane Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000013112 stability test Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GZLGNNHEHXBCBI-UHFFFAOYSA-L [Na+].[Na+].OC(=O)C(O)C(O)C(O)=O.[O-]C(=O)C(O)C(O)C([O-])=O Chemical compound [Na+].[Na+].OC(=O)C(O)C(O)C(O)=O.[O-]C(=O)C(O)C(O)C([O-])=O GZLGNNHEHXBCBI-UHFFFAOYSA-L 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 3
- 239000011780 sodium chloride Chemical group 0.000 description 3
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical group [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010020575 Hyperammonaemia Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical group OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229940057606 carbaglu Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000008103 glucose Chemical group 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000647 trehalose group Chemical group 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960002779 carglumic acid Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006910 ice nucleation Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- BUCIWTBCUUHRHZ-UHFFFAOYSA-K potassium;disodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O BUCIWTBCUUHRHZ-UHFFFAOYSA-K 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a freeze-dried solid preparation of carglutamic acid and a preparation method thereof, wherein raw materials of the freeze-dried solid preparation of carglutamic acid are selected from aqueous solutions of carglutamic acid, and the aqueous solutions of carglutamic acid comprise: kaglutamic acid, excipient, tertiary butanol and water; based on the volume of the aqueous solution of the carboglutamic acid, the content of the excipient is more than 20mg/mL and less than or equal to 75mg/mL; the volume fraction of the tertiary butanol is more than 5 volume percent and less than or equal to 50 volume percent. The freeze-dried solid preparation of the carboglutamic acid has the advantages of strong stability, uniform color, loose appearance, full and complete appearance, quick redissolution, simple and convenient preparation method, easy control and suitability for popularization and application.
Description
Technical Field
The invention relates to the field of medicine. In particular, the invention relates to a freeze-dried solid preparation of carboglutamic acid and a preparation method thereof.
Background
Carbaglu (carglumic acid, chinese name: kaglutamic acid tablet) was marketed in 2010 and was originally approved for the adjuvant treatment of acute hyperammonemia due to acetylglutamate synthase (NAGS) and the maintenance treatment of chronic hyperammonemia. 2021, carbaglu was the first drug to treat hyperammemia caused by acrylic acid (PA) or methylmalonic acid (MMA).
The kaglutamic acid tablet has a problem of high hygroscopicity and unstable chemical properties. For example, an unopened kaglutamic acid tablet vial should be sealed and stored at 2 to 8 ℃. After the first opening, the vial must be stored at a temperature above the refrigerated temperature but below 30 ℃. In addition, any unused tablets must be taken within one month of the first opening of the vial or will fail. For non-oral administration, such as administration by injection into a nasogastric tube for patients who cannot swallow, it is desirable to disperse the glutamate tablets in water and immediately inject them to avoid glutamate failure. Furthermore, no ready-to-use intravenous or injectable sterile formulations of kaglutamic acid have been found. Thus, the use of kaglutamic acid is severely restricted.
Currently, the kaglutamic acid tablets are mostly manufactured by a direct compression method, and the kaglutamic acid-containing tablets are manufactured by a direct compression method as disclosed in EP2777696B1 and CN105056246 a. The kaglutamic acid tablet obtained by the direct compression method is easy to have the defects of high hygroscopicity, unstable chemical properties and the like.
Therefore, the current freeze-dried solid preparation of the carboglutamic acid and a preparation method thereof still remain to be studied.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides the freeze-dried solid preparation of the carglutamic acid and the preparation method thereof, and the freeze-dried solid preparation of the carglutamic acid has the advantages of strong stability, uniform color, loose appearance, full and complete appearance, quick redissolution, simple and convenient preparation method operation and easy control, and is suitable for popularization and application.
In one aspect of the invention, the invention provides a freeze-dried solid preparation of kaglutamic acid. According to an embodiment of the present invention, the raw materials of the freeze-dried solid preparation of kaglutamic acid include an aqueous solution of kaglutamic acid, which includes: kaglutamic acid, excipient, tertiary butanol and water; based on the volume of the aqueous solution of the carboglutamic acid, the content of the excipient is more than 20mg/mL and less than or equal to 75mg/mL; the volume fraction of the tertiary butanol is more than 5 volume percent and less than or equal to 50 volume percent.
According to the embodiment of the invention, the freeze-dried solid preparation of the carboglutamic acid prepared by a freeze-drying method has the advantages of small loss of active ingredients, good resolubility, low hygroscopicity, long storage period and the like compared with the existing direct-pressure method.
The inventor of the present invention has further studied intensively and found that the addition of excipient to raw materials of a lyophilized solid preparation of kaglutamic acid can provide protection for kaglutamic acid during lyophilization, reduce loss, and help to maintain stability of intended function of kaglutamic acid. In the freeze-drying process, the tertiary butanol can form ice crystals, and pore channels are finally formed after the ice crystals sublimate, so that the freeze-dried preparation is quickly dissolved after meeting water, and the re-dissolution time is shortened. And the tertiary butanol can be removed after sublimation, and the tertiary butanol is not in the freeze-dried preparation, so that the hidden danger of use is avoided.
On the basis, the inventor conducts intensive research on the addition amount of the excipient and the tertiary butanol, and discovers that the addition amount of the excipient and the tertiary butanol has great influence on the characteristics of the freeze-dried preparation, and when the content of the excipient is lower than 20mg/mL, the characteristics of the prepared freeze-dried preparation are incomplete and collapse exists; when the excipient content is more than 75mg/mL, the preparation cost is increased; when the content of the excipient is more than 20mg/mL and less than or equal to 75mg/mL, the integral characteristic of the carglutamic acid freeze-dried solid preparation is better, the re-solubility and the stability are good, and the hygroscopicity is improved. The content of tertiary butanol cannot be too low, and when the volume fraction is lower than 5%, the prepared freeze-dried preparation is poor in shape and cannot meet the requirements; the content is too high, the subsequent freeze drying treatment time is correspondingly increased, and when the content of tertiary butanol is more than 5 volume percent and less than or equal to 50 volume percent, the prepared carglutamic acid freeze-dried solid preparation has good form and strong stability. In some preferred embodiments, the tertiary butanol is present in an amount of 10 to 40% by volume, preferably 15 to 30% by volume.
According to an embodiment of the invention, the excipient comprises one or more of trehalose, sucrose and mannitol. The inventor finds out through a large number of experiments that different excipients have great influence on the properties of samples, and when the freeze-dried solid preparation of the carboglutamic acid obtained by adopting the excipients has uniform color, loose appearance and full and complete appearance. Meanwhile, the stability of the freeze-dried solid preparation of the carglutamic acid can be improved, the re-dissolution time is very short, and the freeze-dried solid preparation of the carglutamic acid has excellent comprehensive performance.
According to an embodiment of the present invention, the pH of the aqueous solution of kaglutamic acid is 5.5 to 7.5, more preferably 6.5 to 7.5, and the lyophilized aqueous solution of kaglutamic acid further comprises: buffer salt. The pH value is stabilized at 5.5-7.5 by adding buffer salt. According to an embodiment of the invention, the buffer salt is selected from phosphates. Compared with other buffer salts, the product obtained by adopting phosphate has complete and loose form, strong stability, good resolubility and high clarity. The phosphate buffer system of the present invention may be one or more of disodium hydrogen phosphate-citric acid buffer system, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer system, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer system, potassium dihydrogen phosphate-sodium hydroxide buffer system, and potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer system. According to a preferred embodiment of the invention, the phosphate salts include monopotassium phosphate and dipotassium phosphate. The inventors have studied the long-term stability of the formulation and found that the pH was more stable at the end of the long-term stability test and the accelerated stability test of the formulation prepared with monopotassium phosphate and dipotassium phosphate as buffer salts.
According to an embodiment of the present invention, the aqueous solution of kaglutamic acid comprises the following components based on the total volume of the aqueous solution of kaglutamic acid: the content of the carboglutamic acid is 5-75 mg/mL, preferably 15-35 mg/mL; trehalose, the content of which is 25-45 mg/mL, preferably 25-35 mg/mL; tertiary butanol, the content of which is 10 to 40% by volume, preferably 15 to 30% by volume; and (3) buffering salt, and adjusting the pH value of the aqueous solution of the carbamates to be 5.5-7.5. The inventor obtains the content of the above preferred components through a large number of experiments, and the obtained freeze-dried solid preparation of the carboglutamic acid has the advantages of strong stability, uniform color, loose appearance, full and complete appearance and quick redissolution.
According to the embodiment of the invention, the freeze-dried solid preparation of the carboglutamic acid is a freeze-dried preparation for injection.
In another aspect of the present invention, the present invention provides a method for preparing the aforementioned lyophilized solid preparation of kaglutamic acid. According to an embodiment of the invention, the method comprises: mixing the carfentrazone-ethyl acid, excipient, tertiary butanol, water and optional buffer salt to obtain a carfentrazone-ethyl acid aqueous solution; and carrying out freeze drying treatment on the aqueous solution of the carfentrazone-ethyl acid to obtain the freeze-dried solid preparation of the carfentrazone-ethyl acid.
According to the method provided by the embodiment of the invention, the carboglutamic acid, the excipient, the tertiary butanol, the water and the optional buffer salt are mixed to obtain a uniform carboglutamic acid aqueous solution, and then the carboglutamic acid aqueous solution is subjected to freeze-drying treatment to obtain the carboglutamic acid freeze-dried solid preparation. The use of freeze-drying has at least the following advantages: (1) Ensuring the quality of the medicine and avoiding the thermal deterioration and decomposition of the active ingredients; (2) loosening the texture of the product, and rapidly dissolving the product after adding water; (3) The water content is low, and the filling of inert gas is convenient, which is favorable for medicine storage and prevents hydrolysis, oxidation and microorganism growth.
According to an embodiment of the present invention, the aqueous solution of kaglutamic acid is subjected to sterilization filtration and filling prior to the freeze-drying treatment. Therefore, the pollution of mixed bacteria is avoided, and the quality guarantee period is prolonged.
According to an embodiment of the present invention, the freeze-drying process includes: performing pre-freezing treatment on the aqueous solution of the glutamic acid to obtain a first treated matter; performing sublimation drying treatment on the first treated matter to obtain a second treated matter; and (3) carrying out resolution drying treatment on the second treated matter to obtain the carglutamic acid freeze-dried solid preparation. The aim of prefreezing is to solidify the self-contained water, thus effectively preventing the irreversible changes of air bubbles, concentration and the like in the drying process and leading the product forms before and after drying to be consistent. There are two processes in this process, ice nucleation and ice crystal growth. The sublimation drying (first stage drying) is to dry the pre-frozen product under vacuum, and at the same time, the ice crystals sublimate into water vapor to escape by utilizing the suction effect of a cold trap, so that the product is dehydrated and dried, the sublimation is gradually inwards pushed from the outer surface, and the porous drying layer is left after the ice crystals sublimate and becomes a channel for escaping the water vapor. About 90% of the total moisture was removed by the sublimation drying process. Resolution drying, also known as secondary drying. After the sublimation drying is finished, the material is heated under vacuum, and the material is heated to a higher temperature generally, so that unfrozen bound water in the material absorbs energy and then desorbs water vapor to leave the material.
According to the technical scheme of the invention, the aqueous solution of the carfentrazone-ethyl acid is subjected to freeze-drying treatment to obtain the freeze-dried solid preparation of the carfentrazone-ethyl acid, and the freeze-drying treatment comprises the following steps: performing pre-freezing treatment on the aqueous solution of the glutamic acid to obtain a first treated object, wherein the pre-freezing treatment comprises a cooling step of cooling the aqueous solution of the glutamic acid to below-40 ℃, and the cooling rate of the cooling step is less than 2 ℃/min; performing sublimation drying treatment on the first treated object to obtain a second treated object, wherein the heating rate in the sublimation drying process is lower than 0.5 ℃/min; and (3) carrying out resolution drying treatment on the second treated matter to obtain the carglutamic acid freeze-dried solid preparation.
According to an embodiment of the present invention, the pre-freezing process includes: cooling the aqueous solution of the carboglutamic acid at 15-25 ℃ to-42 to-47 ℃ at a cooling rate of 0.5-1 ℃/min, and preserving heat for 1-3 hours; then heating to-2 to-6 ℃, wherein the heating rate is 1-2 ℃/min, and preserving heat for 1-3 hours; then cooling to-42 to-47 ℃, wherein the cooling rate is 0.5-1 ℃/min, and preserving heat for 1-3 hours. In some embodiments, the pre-freezing process comprises: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 0.5 ℃/min to 1 ℃/min and maintained for 2 hours; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4 ℃ to-45 ℃ at a cooling rate of 0.5 ℃/min to 1 ℃/min and keep for 2 hours.
According to an embodiment of the present invention, the sublimation drying process includes: heating the first treated matter to-6 to-10 ℃ at the speed of 0.05-0.3 ℃/min, and preserving heat for 1-3 hours. In some embodiments, the temperature is raised to-8deg.C at a rate of 0.05-0.1deg.C/min, preferably 0.1deg.C/min, for 2h.
According to an embodiment of the present invention, the resolution drying process includes: heating the second treated matter to 28-32 deg.c and maintaining for 6-10 hr. In some embodiments, the analytical drying process comprises: raising the temperature to 30 ℃ at a rate of 0.2-0.5 ℃/min, preferably 0.5 ℃/min, and keeping for 8h.
The inventor finds that various stresses can be generated in the freeze drying process, and the effects on the drug property, the quality stability and the like of the freeze-dried solid preparation are great, so that the inventor reasonably designs the freeze-dried prescription process to obtain the better prefreezing treatment condition, sublimation drying treatment condition and analytical drying treatment condition, thereby obtaining the freeze-dried solid preparation of the carboglutamic acid, which has stable quality, complete and loose properties, low water content, high re-solubility and safe use. In addition, the energy consumption in the preparation process is low, the cost is reduced, and the method is suitable for large-scale production.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
Mixing trehalose, tertiary butanol, carboglutamic acid and 15-25 ℃ water for injection, stirring uniformly, adding monopotassium phosphate and dipotassium phosphate to adjust the pH value to 7.0, filtering the obtained liquid medicine through a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m, packaging into 50ml glass molded bottles, and half-pressing plugs for each bottle with the thickness of 20 ml. Wherein, in the aseptic aqueous solution of the carbamyl glutamate, the content of the carbamyl glutamate is 25mg/ml, the content of the trehalose is 25mg/ml, the volume fraction of the tertiary butanol is 20 percent, and a proper amount of monopotassium phosphate and dipotassium phosphate are adopted.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 2
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
Mixing trehalose, tertiary butanol, carboglutamic acid and 15-25 ℃ water for injection, stirring uniformly, adding monopotassium phosphate and dipotassium phosphate to adjust the pH value to 7.0, filtering the obtained liquid medicine through a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m, packaging into 50ml glass molded bottles, and half-pressing plugs for each bottle with the thickness of 20 ml. Wherein, in the aseptic aqueous solution of the carbamyl glutamate, the content of the carbamyl glutamate is 25mg/ml, the content of the trehalose is 25mg/ml, the volume fraction of the tertiary butanol is 20 percent, and a proper amount of monopotassium phosphate and dipotassium phosphate are adopted.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 0.5 ℃/min and maintained for 2 hours; heating to-4 ℃ by annealing, wherein the heating rate is 1 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 0.5deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 3
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
Mixing trehalose, tertiary butanol, carboglutamic acid and 15-25 ℃ water for injection, stirring uniformly, adding monopotassium phosphate and dipotassium phosphate to adjust the pH value to 7.0, filtering the obtained liquid medicine through a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m, packaging into 50ml glass molded bottles, and half-pressing plugs for each bottle with the thickness of 20 ml. Wherein, in the aseptic aqueous solution of the carbamyl glutamate, the content of the carbamyl glutamate is 25mg/ml, the content of the trehalose is 25mg/ml, the volume fraction of the tertiary butanol is 20 percent, and a proper amount of monopotassium phosphate and dipotassium phosphate are adopted.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 0.5 ℃/min and maintained for 2 hours; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 0.5deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 4
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
Mixing trehalose, tertiary butanol, carboglutamic acid and 15-25 ℃ water for injection, stirring uniformly, adding monopotassium phosphate and dipotassium phosphate to adjust the pH value to 7.0, filtering the obtained liquid medicine through a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m, packaging into 50ml glass molded bottles, and half-pressing plugs for each bottle with the thickness of 20 ml. Wherein, in the aseptic aqueous solution of the carbamyl glutamate, the content of the carbamyl glutamate is 25mg/ml, the content of the trehalose is 25mg/ml, the volume fraction of the tertiary butanol is 20 percent, and a proper amount of monopotassium phosphate and dipotassium phosphate are adopted.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Examples 1 to 4 were tested, the test contents including: the results of the properties, clarity and reconstitution time are shown in Table 1, and the freeze-dried preparation of the carboglutamic acid for injection prepared in examples 1 to 4 has complete and loose structure, is clarified after being dissolved by water for injection, and has short reconstitution time, wherein the effect of example 1 is better.
Table 1 analytical results for examples 1 to 4
Comparative examples 1 to 3 and examples 5 to 6
A freeze-dried preparation of carboglutamic acid for injection was prepared as in example 1, except that trehalose was replaced with lactose, sodium chloride, glucose, sucrose, mannitol.
Tests were performed on example 1, example 5, example 6 and comparative examples 1 to 3, the test contents including: the properties, clarity, and reconstitution time were as shown in Table 2. The products prepared in example 1, example 5, example 6 and comparative examples 1-3 are not greatly different in color and are uniformly white or white-like, but different excipients have great influence on the properties of the samples, the samples without the excipients are incomplete and layered, and the properties of the samples obtained from lactose, sodium chloride and glucose are poor; clarity except sodium chloride, other samples are clear after redissolution; for reconstitution times, both are longer than trehalose. Compared with the excipient, the sample taking trehalose as the excipient has uniform color, loose appearance, complete fullness and quick redissolution, so that the trehalose is preferably selected as the excipient.
TABLE 2 analysis of different excipients
Examples 7 to 11 and comparative examples 4 to 8
A freeze-dried preparation of carboglutamic acid for injection was prepared as in example 1, except that the amount of trehalose was replaced with 0.0g, 10.0g, 30.0g, 70.0g or 90.0g.
Examples 1, 7, 8 and comparative examples 4-6 were tested, the test contents including: the properties, clarity, and reconstitution time were as shown in Table 3. The excipient trehalose has better effect than the excipient trehalose which is not used, and the trehalose is used in an amount of 25-45 mg/mL. To reduce costs, trehalose is preferably used in an amount of 25mg/mL.
TABLE 3 analysis results of different trehalose addition amounts
A freeze-dried preparation of carboglutamic acid for injection was prepared as in example 1, except that the t-butanol was replaced with 0%, 5%, 10%, 30%, 40%.
Testing the sample, wherein the test content comprises: the properties, clarity, and reconstitution time, and the results are shown in the following table. The tertiary butanol is better than the non-use property, and the tertiary butanol is used in an amount of 10-40% by volume as a feasible amount. Considering the properties, reconstitution time and preparation cost in combination, the preferred amount of t-butanol is 20%.
TABLE 4 analysis of the amounts of t-butanol
Examples 12 to 15 and comparative example 9
In this example, a lyophilized preparation of kaglutamic acid was prepared as in example 1, except that the potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer salt was replaced with citric acid-sodium citrate buffer salt, acetic acid-sodium acetate buffer salt, tartaric acid-sodium tartrate buffer salt, and the aqueous solution of kaglutamic acid was controlled at pH 7.0.
Examples 1, 12-15 and comparative example 9 were tested, the test contents including: the properties, clarity, and reconstitution time were as shown in Table 5. Compared with potassium dihydrogen phosphate-dipotassium hydrogen phosphate and potassium dihydrogen phosphate-sodium hydroxide group samples, the pH of the samples obtained by adopting citric acid-sodium citrate, acetic acid-sodium acetate, tartaric acid-sodium tartrate and no buffer salt is reduced to different degrees, and the properties, clarity and redissolution time are not obviously different.
The pH value of the freeze-dried solid preparation without buffer salt is 3.5, and the pharmacological irritation test shows that the freeze-dried solid preparation without buffer salt has lower pH, larger irritation and increased hemolysis, and has painful feeling during injection (the pH value of normal human blood is kept between 7.35 and 7.45), and the pH range of the general injection is required to be 4-9, so the freeze-dried preparation without buffer salt of the carboglutamic acid does not meet the requirement.
TABLE 5 analysis of the different buffer salts
The six groups of samples were further examined for long-term stability testing (temperature 25.+ -. 2 ℃ C., relative humidity 60%.+ -. 5% RH) and accelerated stability testing (40 ℃ C..+ -. 2 ℃ C., relative humidity 75.+ -. 5% RH). The results are shown in Table 6, and the characteristics of six groups of samples are basically unchanged under the conditions of a long-term stability test and an accelerated stability test; the water content slightly rises, but is not excessive in a prescribed time; the total impurities are in a control range, and the total impurities are in a controllable range at the end of an acceleration stability test although the total impurities are slightly increased; the content of the active ingredients is in the range, and the content is slightly reduced at the end of the accelerated stability test; the pH of the potassium dihydrogen phosphate-dipotassium hydrogen phosphate group at the end of the accelerated stability test is the slowest to drop, and the pH of the potassium dihydrogen phosphate-sodium hydroxide, the three groups of citric acid-sodium citrate, acetic acid-sodium acetate and tartaric acid-sodium tartrate are fast to drop, so that the stability is relatively low, and the product quality is affected to a certain extent. Therefore, potassium dihydrogen phosphate-dipotassium hydrogen phosphate is preferable as the buffer salt.
TABLE 6 stability analysis
Example 16
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 2 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 17
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 0.3 ℃/min and maintained for 2 hours; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 18
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.05 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 19
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.5 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.5℃per minute and maintained for 8 hours.
Example 20
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.2℃per minute and maintained for 8 hours.
Example 21
In this example, a lyophilized preparation of carboglutamic acid for injection was prepared as follows:
1. Preparation of an aqueous sterile carboglutamic acid solution:
As in example 1.
2. And (3) freeze drying:
(a) Pre-freezing: the temperature is reduced from 25 ℃ to-45 ℃ with the cooling rate of 1 ℃/min and maintained for 2h; heating to-4 ℃ by annealing, wherein the heating rate is 1.5 ℃/min, and keeping for 2 hours; the second cooling process is to cool the temperature from-4deg.C to-45deg.C, the cooling rate is 1deg.C/min, and the temperature is maintained for 2h.
(B) Sublimation drying: raising the temperature to-8 ℃ at the speed of 0.1 ℃/min, and keeping for 2 hours.
(C) And (5) analysis and drying: the temperature was raised to 30℃at a rate of 0.8℃per minute and maintained for 8 hours.
The freeze-drying times of the whole examples 1 to 4 and 15 are shown in the following table.
TABLE 7 lyophilization time
Experimental results and conclusions of lyophilization process optimization (pre-lyophilization rate, sublimation drying rate, analytical drying rate, etc.):
The results of the pre-freeze rate screening (example 1, example 2, example 3, example 4, example 16, example 17) are shown in the following table. The prefreezing cooling rate is between 0.5 and 1 ℃/min, the property is complete and loose, and the property is incomplete, blocky crust exists when the rate is higher (2 ℃/min), and the moisture content is higher, so that the sample temperature is excessively lowered, the ice crystal grows finely, the sublimation resistance is high, and the phenomenon of incomplete freezing exists, which is unfavorable for subsequent Hua Gansao; when the pre-freezing cooling rate is slower (0.3 ℃/min), the characteristics are complete and loose, the moisture content is low, but the time is too long and the energy consumption is large, so that the pre-freezing cooling rate is preferably 0.5 ℃/min to 1 ℃/min.
TABLE 8 analysis of prefreezing conditions
The results of the sublimation drying rate screening (examples 1,2, 3, 4, 18 and 19) are shown in the following table, and the sublimation drying rate is between 0.05 ℃/min and 0.1 ℃/min, the properties are complete and loose, the moisture content is low, the properties collapse and crust are found when the rate is higher (0.5 ℃/min), the moisture content is higher, and the reason is probably that the uneven heating is caused when the sublimation drying rate is higher, the crystallization of the lower-layer product cannot be sublimated directly when the uneven heating is caused, but the crystallization is evaporated from solid, liquid to gas, and the upper-lower-layer structure difference of the sample is caused to collapse; at a slower rate (0.05 ℃/min), the properties are complete, loose, the moisture content is low, but the time is too long and the energy consumption is large, so 0.1 ℃/min is preferable.
TABLE 9 analysis of sublimation drying Condition
Analytical drying rate screening (example 1, example 2, example 3, example 4, example 20, example 21) results are shown in the following table. The analysis drying rate is 0.2-0.5 ℃/min, the property is complete and loose, the moisture content is low, and when the rate is faster (0.8 ℃/min), the property is found to be slightly layered, the moisture content is higher, and the reason is probably caused by uneven heating when the analysis drying rate is faster; at a slower rate (0.2 ℃/min), the properties are complete, loose, the moisture content is low, but the time is too long and the energy consumption is large, so 0.5 ℃/min is preferred.
Table 10 analysis of drying conditions
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (12)
1. The freeze-dried solid preparation of the carglutamic acid is characterized in that raw materials of the freeze-dried solid preparation of the carglutamic acid comprise aqueous solutions of the carglutamic acid, and the aqueous solutions of the carglutamic acid comprise:
kaglutamic acid, excipient, tertiary butanol and water;
based on the volume of the aqueous solution of the carboglutamic acid, the content of the excipient is more than 20mg/mL and less than or equal to 75mg/mL; the volume fraction of the tertiary butanol is more than 5 volume percent and less than or equal to 50 volume percent;
the excipient comprises trehalose;
in the aqueous solution of the carboglutamic acid, the content of the carboglutamic acid is 5-75 mg/mL.
2. The solid lyophilized kaglutamic acid preparation according to claim 1, wherein the aqueous solution of kaglutamic acid has a pH of 5.5 to 7.5, and the aqueous solution of kaglutamic acid further comprises: buffer salt.
3. The lyophilized solid formulation of kaglutamic acid according to claim 2, wherein the buffer salt is selected from phosphates.
4. A lyophilized solid preparation of kaglutamic acid as claimed in claim 3, wherein the phosphate comprises monobasic potassium phosphate and dibasic potassium phosphate.
5. The lyophilized solid preparation of kaglutamic acid according to claim 1, wherein the aqueous solution of kaglutamic acid comprises the following components based on the total volume of the aqueous solution of kaglutamic acid:
the content of the carboglutamic acid is 5-75 mg/mL;
Trehalose, wherein the content of the trehalose is 25-45 mg/mL;
tertiary butanol, wherein the content of the tertiary butanol is 10-40% by volume;
And (3) buffering salt, and adjusting the pH value of the aqueous solution of the carbamates to be 5.5-7.5.
6. The solid lyophilized preparation of carglutamic acid according to claim 1, wherein the content of the carglutamic acid is 15-35 mg/mL;
the content of the trehalose is 25-35 mg/mL;
The content of the tertiary butanol is 15-30% by volume.
7. The lyophilized solid formulation of kaglutamic acid according to claim 1, wherein the lyophilized solid formulation of kaglutamic acid is a lyophilized formulation for injection.
8. A method for preparing the freeze-dried solid preparation of kaglutamic acid according to any one of claims 1 to 7, which comprises:
mixing the carfentrazone-ethyl acid, excipient, tertiary butanol, water and optional buffer salt to obtain a carfentrazone-ethyl acid aqueous solution;
and carrying out freeze drying treatment on the aqueous solution of the carfentrazone-ethyl acid to obtain the freeze-dried solid preparation of the carfentrazone-ethyl acid.
9. The method of claim 8, wherein the freeze-drying process comprises:
performing pre-freezing treatment on the aqueous solution of the glutamic acid to obtain a first treated object, wherein the pre-freezing treatment comprises a cooling step of cooling the aqueous solution of the glutamic acid to below-40 ℃, and the cooling rate of the cooling step is less than 2 ℃/min;
Performing sublimation drying treatment on the first treated object to obtain a second treated object, wherein the heating rate in the sublimation drying process is lower than 0.5 ℃/min;
and (3) carrying out resolution drying treatment on the second treated matter to obtain the carglutamic acid freeze-dried solid preparation.
10. The method of claim 9, wherein the pre-freezing process comprises:
Cooling the aqueous solution of the carboglutamic acid at 15-25 ℃ to-42 to-47 ℃ at a cooling rate of 0.5-1 ℃/min, and preserving heat for 1-3 hours; then heating to-2 to-6 ℃, wherein the heating rate is 1-2 ℃/min, and preserving heat for 1-3 hours; and then cooling to-42 to-47 ℃, wherein the cooling rate is 0.5-1 ℃/min, and preserving heat for 1-3 hours.
11. The method of claim 9, wherein the sublimation drying process comprises:
And heating the first treated object to-6 to-10 ℃ at a speed of 0.05-0.3 ℃/min, and preserving heat for 1-3 hours.
12. The method of claim 9, wherein the analytical drying process comprises:
And heating the second treated object to 28-32 ℃ at the speed of 0.2-0.5 ℃/min, and preserving heat for 6-10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211496715.1A CN115770225B (en) | 2022-11-25 | 2022-11-25 | Cardiglutamic acid freeze-dried solid preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211496715.1A CN115770225B (en) | 2022-11-25 | 2022-11-25 | Cardiglutamic acid freeze-dried solid preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115770225A CN115770225A (en) | 2023-03-10 |
| CN115770225B true CN115770225B (en) | 2024-09-17 |
Family
ID=85390350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211496715.1A Active CN115770225B (en) | 2022-11-25 | 2022-11-25 | Cardiglutamic acid freeze-dried solid preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115770225B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1112347A (en) * | 1965-08-20 | 1968-05-01 | Pierre Wirth | Salts of organic bases with n-carbamyl-l-glutamic acid |
| EP3323410A1 (en) * | 2016-11-22 | 2018-05-23 | RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a. | Pharmaceutical parenteral formulation containing carglumic acid |
| CN108165522B (en) * | 2017-12-28 | 2020-12-01 | 中国农业科学院饲料研究所 | Embryonic-period supplement for improving quality of broiler chickens and promoting early growth and application thereof |
-
2022
- 2022-11-25 CN CN202211496715.1A patent/CN115770225B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| 姚静等.药物冻干制剂技术的设计与应用.中国医药科技出版社,2007,(第1版),89. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115770225A (en) | 2023-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI548414B (en) | Daptomycin compositions and related methods | |
| AU713599B2 (en) | Methods for stably incorporating substances within dry, foamed glass matrices and compositions obtained thereby | |
| CA2037884C (en) | Stabilized gonadotropin containing preparations | |
| CN100484525C (en) | Pantoprazole sodium freeze-dried powder injection and preparing method thereof | |
| CN101627996B (en) | Rabeprazole sodium composition and preparation method thereof | |
| CN112361726B (en) | Freeze-dried preparation water control method and application thereof | |
| CN101224196A (en) | Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof | |
| CN115770225B (en) | Cardiglutamic acid freeze-dried solid preparation and preparation method thereof | |
| CN102228444B (en) | N(2)-L-alanyl-L-glutamine preparation for injection and preparation method thereof | |
| CN104127410A (en) | Ornidazole injection liquid | |
| CN101229133A (en) | Omeprazole sodium freeze-dried powder injection and preparing method thereof | |
| CN111375052A (en) | Freeze-drying method of freeze-dried preparation of azadirachtin for injection | |
| WO2023174991A1 (en) | Continuous spin freeze-drying of nucleic acid containing compositions | |
| CN114931648B (en) | Heat-resistant protective agent for combined live vaccine against porcine epidemic diarrhea and transmissible gastroenteritis, and preparation method and application thereof | |
| CN102512382B (en) | Esomeprazole sodium pharmaceutical composition for injection | |
| CN102166198A (en) | Stable naloxone hydrochloride freeze-dry preparation and preparation method thereof | |
| CN113274361B (en) | Nicotinamide freeze-dried powder injection and preparation method thereof | |
| CN113730360A (en) | Freeze-drying method for preparing coenzyme A | |
| CN115581675B (en) | Preparation method of clindamycin phosphate for injection | |
| CN112655769A (en) | Human milk flash-release tablet and preparation method thereof | |
| CN115444826B (en) | Preparation method of pantoprazole sodium for injection | |
| CN113041226A (en) | Preparation process of pantoprazole sodium for injection | |
| CN111643460A (en) | Pantoprazole sodium freeze-dried preparation, preparation method thereof and injection preparation prepared from pantoprazole sodium freeze-dried preparation | |
| CN104771374A (en) | Preparation method of lactobionic acid azithromycin freeze-dried powder injection for injection and freeze-dried powder injection prepared by preparation method | |
| CN114177147B (en) | Preparation method of terlipressin for injection and terlipressin for injection prepared by preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |